Brain Advance Access originally published online on December 5, 2005
Brain 2006 129(2):399-410; doi:10.1093/brain/awh702
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The association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and morphological abnormalities of the brain in chronic schizophrenia
1 Department of Radiology, National Center Hospital of Mental, Nervous and Muscular Disorders, National Center of Neurology and Psychiatry, 2 Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 3 Department of Psychiatry, National Center Hospital of Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Tokyo and 4 Department of Investigative Radiology, Research Institute, National Cardiovascular Center, Osaka, Japan
Correspondence to: Takashi Ohnishi, Department of Radiology, National Center Hospital of Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry 4-1-1 Ogawa Higashi, Kodaira City, Tokyo, Japan 187-0031 E-mail: tohnishi{at}hotmail.com
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Summary |
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The catechol-O-methyl transferase (COMT) gene is considered to be a promising schizophrenia susceptibility gene. A common functional polymorphism (Val158Met) in the COMT gene affects dopamine regulation in the prefrontal cortex (PFC). Recent studies suggest that this polymorphism contributes to poor prefrontal functions, particularly working memory, in both normal individuals and patients with schizophrenia. However, possible morphological changes underlying such functional impairments remain to be clarified. The aim of this study was to examine whether the Val158Met polymorphism of the COMT gene has an impact on brain morphology in normal individuals and patients with schizophrenia. The Val158Met COMT genotype was obtained for 76 healthy controls and 47 schizophrenics. The diagnostic effects, the effects of COMT genotype and the genotype-diagnosis interaction on brain morphology were evaluated by using a voxel-by-voxel statistical analysis for high-resolution MRI, a tensor-based morphometry. Patients with schizophrenia demonstrated a significant reduction of volumes in the limbic and paralimbic systems, neocortical areas and the subcortical regions. Individuals homozygous for the Val-COMT allele demonstrated significant reduction of volumes in the left anterior cingulate cortex (ACC) and the right middle temporal gyrus (MTG) compared to Met-COMT carriers. Significant genotype-diagnosis interaction effects on brain morphology were noted in the left ACC, the left parahippocampal gyrus and the left amygdala-uncus. No significant genotype effects or genotype-diagnosis interaction effects on morphology in the dorsolateral PFC (DLPFC) were found. In the control group, no significant genotype effects on brain morphology were found. Schizophrenics homozygous for the Val-COMT showed a significant reduction of volumes in the bilateral ACC, left amygdala-uncus, right MTG and left thalamus compared to Met-COMT schizophrenics. Our findings suggest that the Val158Met polymorphism of the COMT gene might contribute to morphological abnormalities in schizophrenia.
Key Words: schizophrenia; polymorphism; COMT; ACC; DLPFC
Abbreviations: ACC = anterior cingulate cortex; COMT = catechol-O-methyl transferase; DLPFC = dorsolateral prefrontal cortex; FDR = false discovery rate; IQ = intelligence quotient; JART = Japanese version of National Adult Reading Test; ROI = region of interest; SPM = statistical parametric mapping; TBM = tensor-based morphometry
Received July 15, 2005. Revised September 21, 2005. Accepted October 27, 2005.
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Introduction |
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Schizophrenia is a severe neuropsychiatric disorder with deficits of multiple domains of cognitive functions, volition and emotion. Family and twin studies have provided cumulative evidence for a genetic basis of schizophrenia (Kendler, 1983
; McGue et al., 1983; Sullivan et al., 2003); however, identification of the underlying susceptibility loci has been limited. Collective data have suggested that the aetiology of schizophrenia involves the interplay of complex polygenic influences and environmental risk factors operating on brain maturational processes (Harrison et al., 2005).
In vivo neuroimaging studies have demonstrated that brain abnormalities should play an important role in the pathophysiology of schizophrenia. Structural MRI studies have demonstrated relatively consistent brain abnormalities in patients with schizophrenia, such as enlargement of the ventricular system and regional volume decrease in the temporal lobe structures (Gaser et al., 2001; Okubo et al., 2001; Shenton et al., 2001; Davidson and Heinrichs, 2003). Studies with schizophrenics and their healthy siblings demonstrate that even healthy siblings share some of morphological abnormalities observed in schizophrenia (Steel et al., 2002; Gogtay et al., 2003). A recent morphological MR study revealed that a common polymorphism of the brain-derived neurotrophic factor, one of the well-known schizophrenia susceptibility genes, affected the anatomy of the hippocampus and prefrontal cortex (PFC) in healthy individuals (Pezawas et al., 2004). Furthermore, some studies have suggested that environmental factors interact with genetic factors (Cannon et al., 1993; Nelson et al., 2004). For example, obstetric complications are well known non-genetic risk factors of schizophrenia. However, a previous study suggested that obstetric complications might induce brain morphological abnormalities in schizophrenics and their siblings, but not in comparison with subjects at low genetic risk for schizophrenia (Cannon et al., 1993). These facts suggest that genetic factors should have considerable impact on brain morphology in patients with schizophrenia.
Catechol-O-methyl transferase (COMT) is a promising schizophrenia susceptibility gene because of its role in monoamine metabolism (Goldberg et al., 2003; Stefanis et al., 2004; Harrison et al., 2005). A common single nucleotide polymorphism (SNP) of the COMT gene producing an amino acid substitution of methionine (met) to valine (val) at position 108/158 (Val158Met) affects dopamine regulation in the PFC (Palmatier et al., 1999). This polymorphism impacts on the stability of the enzyme, such that the Val-COMT allele has significantly lower enzyme activity than the Met-COMT allele (Weinberger et al., 2001; Chen et al., 2004). Several studies have revealed that the Val-COMT allele is associated with poorer performances, compared to the Met-COMT allele, in cognitive tasks of frontal function such as the Wisconsin Card Sorting Test (WCST) and N-back task (Egan et al., 2001; Weinberger et al., 2001; Goldberg et al., 2003). The underlying mechanism of such behavioural differences may be related to lower prefrontal dopamine levels arising from higher dopamine catabolism mediated by the Val-COMT allele (Chen et al., 2004; Tunbridge et al., 2004).
The results of studies on the association between the Val158Met polymorphism and schizophrenia have, however, been controversial (Daniels et al., 1996; Kunugi et al., 1997; Ohmori et al., 1998; Norton et al., 2002; Galderisi et al., 2005; Ho et al., 2005). The result of a meta-analysis was even more inconclusive (Fan et al., 2005). Such inconsistency was also found in associations between frontal functions and the Val158Met polymorphism (Egan et al., 2001; Weinberger et al., 2001; Goldberg et al., 2003; Ho et al., 2005). The possible morphological changes due to the COMT gene might be present and play a role in susceptibility to schizophrenia and in giving rise to impaired frontal functions. However, morphological changes underlying functional impairments remain to be clarified.
A recent advancement of methods for MR volumetry, such as voxel-based morphometry and deformation-based morphometry [or tensor-based morphometry (TBM)], allows us to explore and analyse brain structures of schizophrenics (Wright et al., 1995; Gaser et al., 2001). Using TBM techniques, we investigated the association between the Val158Met polymorphism of the COMT gene and brain morphology in normal individuals and patients with schizophrenia. The aim of this study was to clarify whether there are significant genotype and/or genotype-disease interaction effects on brain morphology.
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Subjects
Seventy-six healthy subjects and forty-seven patients with schizophrenia participated in the study. All the subjects were biologically unrelated Japanese. Written informed consent was obtained from all the subjects in accordance with ethical guidelines set by a local ethical committee. All normal subjects were screened using a questionnaire on medical history and excluded if they had neurological, psychiatric or medical conditions that could potentially affect the CNS, such as substance abuse or dependence, atypical headache, head trauma with loss of consciousness, asymptomatic or symptomatic cerebral infarctions detected by T2-weighted MRI, hypertension, chronic lung disease, kidney disease, chronic hepatic disease, cancer, or diabetes mellitus. The patients were diagnosed on the basis of DSM-IV criteria, information from medical records and a clinical interview. All patients were stable and/or partially remitted at the time of MR measurement and neuropsychological tests.
According to genotypes, each group (control and schizophrenia) was categorized into three groups; the homozygous Val-COMT group (control: n = 38, two were left-handed, schizophrenia: n = 19, one was left-handed), the Val/Met-COMT group (control: n = 25, three were left-handed, schizophrenia: n = 22, all were right-handed) and the remaining homozygous Met-COMT group (control: n = 13, all were right-handed, schizophrenia: n = 6, all were right-handed). Because of the small number of subjects with homozygous Met-COMT, the Val/Met-COMT and homozygous Met-COMT groups were combined and treated as one group, the Met-COMT carriers. Table 1 shows the characteristics of each group. All groups were of comparable age, gender (
2 test, df = 3, P = 0.38) and handedness (2-test, df = 3, P = 0.53). No genotype effects and genotype-diagnosis interaction effects were found in years of education, scores of full scale Intelligence Quotient (IQ) and scores of premorbid IQ [Japanese version of National Adult Reading Test (JART) score], however, patients who had fewer years of education (P < 0.0001), had lower scores of both full scale IQ and JART (P < 0.001). The duration of illness, medication and hospitalization, the age at disease onset and drug dose (chlorpromazine equivalent) of those homozygous for the Val-COMT did not differ from the Met-COMT carriers.
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SNP genotyping
Venous blood was drawn from subjects and genomic DNA was extracted from whole blood according to the standard procedures. The Val158Met polymorphism of the COMT gene (dbSNP accession: rs4680) was genotyped using the TaqMan 5'-exonuclease allelic discrimination assay, described previously (Hashimoto et al., 2004, 2005
). Briefly, primers and probes for detection of the SNP are: forward primer 5'-GACTGTGCCGCCATCAC-3', reverse primer 5'-CAGGCATGCACACCTTGTC-3', probe 1 5'-VIC-TTTCGCTGGCGTGAAG-MGB-3' and probe 2 5'-FAM-CGCTGGCATGAAG-MGB-3'. PCR cycling conditions were: at 95°C for 10 min, 50 cycles of 92°C for 15 s and 60°C for 1 min.
MRI procedures
All MR studies were performed on a 1.5 tesla Siemens Magnetom Vision plus system. A three dimensional (3D) volumetric acquisition of a T1-weighted gradient echo sequence produced a gapless series of thin sagittal sections using an MPRage sequence (TE/TR, 4.4/11.4 ms; flip angle, 15°; acquisition matrix, 256 x 256; 1 NEX, field of view, 31.5 cm; slice thickness, 1.23 mm).
Image analysis (TBM)
The basic principle of TBM is to analyse the local deformations of an image and to infer local differences in brain structure. In TBM, MRI scans of individual subjects are mapped to a template image with three-dimensional (3D) non-linear normalization routines. Local deformations were estimated by a univariate Jacobian approach. The basic principle of TBM is the same as a method used in a previous report described as deformation-based morphometry (Gaser et al., 2001). Firstly, inhomogeneities in MR images were corrected using a bias correction function in statistical parametric mapping (SPM2), then the corrected image was scalp-edited by masking with a probability image of brain tissue obtained from each image using a segmentation function in SPM2. Using a linear normalization algorithm in SPM2, all brains were resized to a voxel size of 1.5 mm and adjusted for orientation and overall width, length and height (Fig. 1A). Therefore, brains were transformed to the anatomical space of a template brain whose space is based on Talairach space (Talairach and Tournoux, 1988). Subsequent non-linear normalization introduced local deformations to each brain to match it to the same scalp-edited template brain (Fig. 1C). The non-linear transformation was done using the high-dimension-warping algorithm (Ashburner and Friston, 2004). After the high dimensional warping, each image (Fig. 1B) looks similar to the template (Fig. 1C). Figure 2 demonstrated a mean MR image of 76 controls (left) and a mean MR image of 47 schizophrenics after high dimensional warping (Fig. 2). We obtained 3D deformation fields for every brain (Fig. 1D). Each of these 3D deformation fields consists of displacement vectors for every voxel, which describe the 3D displacement needed to locally deform the brain to match it to the template. We calculated the Jacobian determinants to obtain voxel by voxel parametric maps of local volume change relative to the template brain (Fig. 1E). The local Jacobian determinant is a parameter commonly used in continuum mechanics (Gurtin, 1987), which characterizes volume changes, such as local shrinkage or enlargement caused by warping. The parametric maps of Jacobian determinants were analysed using SPM2, which implements a ‘general linear model’. To test hypotheses about regional population effects and interaction, data were analysed by an analysis of covariance (ANCOVA) without global normalization. There was no significant difference in age among the four groups, however, patients with schizophrenia, particularly those homozygous for the Val-COMT allele, were older than controls. Therefore, we treated age and years of education and scores of JART as nuisance variables. Since TBM explores the entire brain (grey matter, CSF space and white matter) at once, the search volume of TBM has a large number of voxels and since our interest was in morphological changes in the grey matter and CSF space, we excluded white matter tissue from analyses by using an explicit mask (Fig. 1F). We used P < 0.001, corrected for multiple comparisons with false discovery rate (FDR) <0.05 as a statistical threshold. The resulting sets of t values constituted the statistical parametric maps {SPM (t)}. Firstly, we estimated the main effects, the genotype effect in total subjects (the Val/Val-COMT versus the Met-COMT carriers) and the diagnostic effect (schizophrenia versus controls) and then the genotype-diagnosis interaction effect was estimated. Furthermore, the effects of genotypes in each group (controls carrying the Val/Val-COMT gene versus controls carrying the Met-COMT gene and schizophrenics carrying the Val/Val-COMT gene versus schizophrenics carrying the Met-COMT gene) were estimated within the ANCOVA design matrix. Anatomical localization accorded both to MNI coordinates and Talairach coordinates obtained from M. Brett's transformations (www.mrc-cbu.cam.ac.uk/Imaging/mnispace.html) and are presented as Talairach coordinates (Talairach and Tournoux, 1988). Since previous studies have demonstrated the association between the Val158Met polymorphism and the dorsolateral PFC (DLPFC), we applied an additional hypothesis-driven region of interest (ROI) method to test regional population effects in the DLPFC. For this ROI analysis, we used the Wake Forest University PickAtlas (Maldjian et al., 2003) within the ANCOVA design matrix for SPM analysis. We set P < 0.05 (uncorrected) with a small volume correction (P < 0.05 within the ROI) to assess grey matter volume changes in the DLPFC (Brodmann area 46, 9 and 8).
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Results |
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Behavioural data
Patients had a lower full scale IQ, measured by the Wechsler Adult Intelligence Scale—Revised, than controls. They also had a lower expected premorbid IQ measured by a JART, lower scores of Wechsler Memory Scale—Revised and demonstrated poorer performance of working memory measures such as the number of preservative errors in the WCST and digit span (Table 1). No genotype or genotype-diagnosis interaction effects were found in working memory measures and IQ, however, a significant genotype-by-diagnosis interaction effect was found in a visual memory measure (F = 4.605, df = 1, P = 0.03) (Table 1). However, a post hoc t-test (Bonferroni test) demonstrated no genotype effect in each diagnostic category (control: P = 0.15, schizophrenia: P = 0.11).
Morphological changes in schizophrenia (diagnosis effects)
In comparison with controls, patients with schizophrenia demonstrated a significant reduction of volumes in multiple brain areas, such as the limbic and paralimbic systems, neocortical areas and the subcortical regions (Table 2 and Fig. 3). In the limbic and paralimbic systems, patients with schizophrenia showed reduction of volumes in the parahippocampal gyri, amygdala-uncus, insular cortices and the anterior cingulate cortices (ACC). They also demonstrated reduced volumes in the frontal and temporal association areas, dorsal premotor areas and the left thalamus. In comparison with controls, patients with schizophrenia showed significantly increased volume in the CSF space such as lateral ventricle, sylvian and the interhemispheric fissures but not in the grey matter (Table 2 and Fig. 4).
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Morphological changes associated with the Val158Met polymorphism (genotype effects)
In comparison with Met-COMT carriers, individuals homozygous for the Val-COMT allele demonstrated a significant reduction of volumes in the left ACC and the right middle temporal gyrus (MTG) (Table 2 and Fig. 5). The hypothesis-driven analysis demonstrated a genotype effect on volumes in the bilateral DLPFC (right BA9, left BA8) at a lenient threshold (uncorrected P = 0.05) (data are not shown), however, no voxels could survive after the correction for multiple comparisons (FDR < 0.05) within the ROI. There were no areas that individuals homozygous for the Val-COMT allele demonstrated a significant increment of volume compared to Met-COMT carriers.
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Genotype—diagnosis interaction effects
We found significant genotype-diagnosis interaction effects on brain morphology. The stronger effects of Val158Met polymorphism on brain morphology in schizophrenia than those in controls were noted in the left ACC and the left amygdala-uncus (Table 2 and Fig. 6). The hypothesis-driven analysis demonstrated a genotype-diagnosis interaction effect on the volume of the right DLPFC (BA9/46) at a lenient threshold (uncorrected P = 0.05) (data not shown), however, no voxels could survive after the correction of multiple comparisons (FDR < 0.05) within the ROI.
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Effects of the Val58Met polymorphism on brain morphology
Since genotype–disease interaction effects were found, we estimated the effects of genotypes on brain morphology in the control groups and the schizophrenic groups separately. In the control group, we found no significant morphological differences between individuals homozygous for the Val-COMT allele and Met-COMT carriers. Even the hypothesis driven analysis with a lenient statistical threshold (P < 0.05) could not detect any significant morphological changes in the DLPFC between the two groups. Contrary to the control group, schizophrenics homozygous for the Val-COMT allele showed a significant reduction of volumes in the left amygdala-uncus, bilateral ACC, right MTG and the left thalamus when compared to the patients carrying the Met-COMT allele (Table 2, Fig. 7). The hypothesis-driven analysis demonstrated a significantly decreased volume of the bilateral DLPFC in schizophrenics homozygous for the Val-COMT allele when compared to the Met-COMT schizophrenics at a lenient threshold (uncorrected P = 0.05) (data not shown). However, no voxels could survive after the correction for multiple comparisons (FDR < 0.05) within the ROI. There are no significantly increased volumes in the schizophrenics homozygous for the Val-COMT allele. All the results were essentially unchanged even if all the left-handed subjects were excluded in all analyses (data not shown).
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Discussion |
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In this study, we found reduction of volumes in the limbic and paralimbic systems, neocortical areas (prefrontal and temporal cortices) and thalamus in patients with schizophrenia when compared to control subjects. The schizophrenia patients demonstrated a significant enlargement of CSF spaces including the lateral and sylvian fissure, which could be interpreted as a result of impaired neurodevelopment and/or global brain atrophy. These findings are concordant with previous studies of MR morphometry of schizophrenia. According to a recent review and meta-analyses of the morphometry of schizophrenia, the consistent abnormalities in schizophrenia are as follows; (i) ventricular enlargement (lateral and third ventricles); (ii) medial temporal lobe involvement; (iii) superior temporal gyrus involvement (iv) parietal lobe involvement; and (v) subcortical brain region involvement including the thalamus (Okubo et al., 2001
; Shenton et al., 2001; Davidson and Heinrichs, 2003). The other regions observed in this study, such as the insula, DLPFC and the ACC have also often been demonstrated as abnormal areas in schizophrenia (Shenton et al., 2001; Takahashi et al., 2004; Yamasue et al., 2004). Using the TBM technique, we replicated the morphological abnormalities observed in previous MR studies on schizophrenia, suggesting that TBM was able to detect morphological changes associated with this disease. As well as neuroimaging studies, post-mortem studies have also reported morphological abnormalities in schizophrenia, but not necessarily as common neuropathological features. Regions including the hippocampus, ACC, thalamus and the DLPFC are regularly associated with abnormalities of cell size, cell number and neuronal organization (Bogerts, 1993; Arnold and Trojanowski, 1996; Selemon, 2001; Selemon and Lynn, 2002, 2003). Selemon et al. reported that schizophrenics demonstrated abnormalities in overall and laminar neuronal density in the DLPFC (Brodmann area 9) and suggested that the DLPFC should be a particularly vulnerable target in the disease process (Selemon 2001; Selemon and Lynn, 2002, 2003).
Importantly, our results suggest that some of the morphological changes in schizophrenia mentioned above are associated with the Val158Met polymorphism of the COMT gene. In the schizophrenic group, the polymorphism was associated with the volumes in the limbic and paralimbic systems, temporal cortices and the left thalamus, whereas no morphological changes related to the polymorphism were found in normal individuals. As a consequence, significant genotype-diagnosis interaction effects were found in the left ACC and the amygdala-uncus. These results indicate that the Val158Met polymorphism of the COMT gene is strongly associated with morphological changes in schizophrenia, particularly those in the limbic and paralimbic systems. Longitudinal MRI studies of schizophrenia strongly suggest that progressive changes should occur after onset of the illness (Okubo et al., 2001; Ho et al., 2003). Recent studies have demonstrated that antipsychotic drugs, particularly haloperidol, have considerable effects on brain morphology (Arango et al., 2003; Lieberman, 2005; Dorph et al., 2005). Because of the long duration of illness and medication taken by our subjects, the effects of antipsychotics may be a possible confounding factor for our findings. However, the duration of medication and the dose of antipsychotics taken by the Val/Val-COMT schizophrenics did not differ from those of the Met-COMT schizophrenics. Although the effects of antipsychotics on brain morphology may contribute to the observed morphological changes in patients with schizophrenia in this study, it is unlikely that the effects of antipsychotics contributed to morphological differences between the two schizophrenic groups.
When we were preparing this manuscript, another study demonstrated no genotype and genotype-diagnosis interaction effects of the Val158Met polymorphism on morphology of the frontal lobe in controls and schizophrenia (Ho et al., 2005). Although there are differences between the two studies, such as mean ages of subjects, duration of illness, methods for image analysis and a racial factor (Caucasians versus Japanese), that study also demonstrated no genotype and genotype-diagnosis interaction effects on morphology of the DLPFC. However, we found these effects on DLPFC morphology at a very lenient statistical threshold. Further studies with a larger sample will clarify whether Val158Met polymorphism does affect DLPFC morphology. As well as prefrontal morphology, we found no significant genotype or genotype-diagnosis interaction effects on working memory, however, schizophrenics homozygous for the Val-COMT allele tended to have poorer performances on working memory measures, compared to Met-COMT carriers with schizophrenia. Although there were no significant effects of Val158Met polymorphism on working memory and other neuropsychological measures, a significant effect of the polymorphism was noted in brain morphology. The brain morphology has been considered to be useful as an intermediate phenotype in genetic research in neuropsychiatric disorders (Baare et al., 2001; Durston et al., 2005). Therefore, morphological changes might be more sensitive to the effects of genotype than behavioural measures such as the performance of working memory measures. In a previous study (Ho et al., 2005) a similar phenomenon—no significant effect of Val158Met polymorphism on working memory performance but significant effects on brain activities during a working memory task—was found. Further studies with a larger sample size are needed to clarify whether morphological changes are a more sensitive marker of genotype effects than behavioural measures.
Unexpectedly, we found effects of the polymorphism on the ACC volume rather than the DLPFC which is crucial for working memory. Since the ACC is associated with a variety of cognitive tasks involving mental efforts, and also plays important roles in working memory (Paus et al., 2001; Kondo et al., 2004), it is feasible that the Val158Met polymorphism may be associated with the ACC morphology. In fact, a previous study demonstrated that the Val-COMT allele was associated with abnormal ACC function as well as abnormal prefrontal cortical function, relative to the Met-COMT allele, as measured by cognitive tests and fMRI activation in normal subjects (Egan et al., 2001).
One would argue that the effects of one polymorphism of the gene could not explain the morphological changes in schizophrenia. As well as the effects of the Val158Met polymorphism, we agree that other polymorphisms of schizophrenia susceptibility genes and genotype–genotype interaction may relate to individual brain morphology. Such interactions might contribute to the different effects of the Val158Met polymorphism on brain morphology observed in this study. Further studies of each effect and interaction of several schizophrenia susceptibility genes on brain morphology, brain functions and performances of neuropsychological tests should be conducted to clarify how polymorphisms of these genes affect intermediate phenotypes of schizophrenia.
In conclusion, we found an association between the Val158Met polymorphism and morphological abnormalities in schizophrenia. Although the underlying mechanisms of our observation remain to be clarified, our data indicate that brain morphology as an intermediate phenotype should be useful for investigating how genotypes affect endophenotypes of schizophrenia.
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Acknowledgements |
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This study was supported by the Promotion of Fundamental Studies in Health Science of Organization for Pharmaceuticals and Medical Devices Agency. This work was also supported in part by Grants-in-Aid from the Japanese Ministry of Health, Labor and Welfare (H17-kokoro-007 and H16-kokoro-002), the Japanese Ministry of Education, Culture, Sports, Science and Technology and Core research for Evolutional Science and Technology of Japan Science and Technology Agency, Japan Foundation for Neuroscience and Mental Health.
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